Dr. Victor Ogungbe is leading a five-year, $3.67 million research project funded by the National Institutes of Health to develop antiviral treatments that protect the blood-brain barrier from alphavirus infections. The research targets viral replication mechanisms to address mosquito-borne threats with currently no approved human treatments.
Mosquito-borne arboviruses present severe public health challenges due to their ability to invade the central nervous system, where they can cause profound neurological complications. While outbreaks emerge globally, medical countermeasures remain remarkably scarce. There are currently no approved vaccines or therapeutics available for human use against alphaviruses. To confront this gap, researchers at The University of Alabama in Huntsville are advancing a sustained scientific initiative to engineer targeted interventions.
Targeting Viral Replication via Nonstructural Protein 2 Protease
The newly funded initiative centers on the nonstructural protein 2 (nsP2) protease, a vital viral component that drives alphavirus replication. Operating much like molecular scissors, the nsP2 protease cleaves viral polyproteins into the precise fragments required for the pathogen to reproduce and spread throughout a host organism.
By blocking this specific enzymatic activity, the investigative team aims to halt viral multiplication at its source. Previous scientific evaluations established a foundational proof-of-concept, demonstrating that candidate compounds can inhibit alphavirus replication in cell cultures and protect animal models from infection.
Our approach differs in that we are laser-focused on advancing very selective nsP2 protease inhibitors toward development, and we have a chemical space that is synthetically accessible, modular and scalable.
Dr. Victor Ogungbe, an associate professor of chemistry and UAH alumnus
The project objectives focus on two primary milestones. First, researchers will refine lead compounds through structure-activity relationship studies informed by animal model testing. Second, the team will assess whether these antiviral agents preserve the integrity of the blood-brain barrier during active infection.
Preserving the Blood-Brain Barrier Using Organ-on-a-Chip Models
Severe viral infections often trigger systemic inflammation that compromises the blood-brain barrier, increasing its permeability and contributing directly to brain swelling and neurological injury. Understanding whether early antiviral administration can mitigate this structural damage is central to reducing long-term neurological consequences.
To evaluate these dynamics without the technical and financial hurdles of traditional animal testing, the researchers are incorporating organ-on-a-chip models developed in collaboration with Professor Aarthi Narayanan of George Mason University. These laboratory systems replicate human tissue architecture under controlled conditions, permitting repeated sampling on both sides of the barrier to monitor permeability changes and viral particle loads simultaneously.
Organ-on-a-chip models provide a way to study the blood-brain barrier in ways that are very challenging in animal models. We can do repeated sampling on both sides of the barrier to check permeability and viral particle levels, which is currently very costly and technically limiting in animal models. This is especially true when evaluating multiple inhibitors at different doses.
Dr. Victor Ogungbe, an associate professor of chemistry and UAH alumnus
Venezuelan Equine Encephalitis Virus Impairs Neurite Outgrowth
At the cellular level, independent modeling using human induced pluripotent stem cell-derived neurospheres reveals that both neurons and glial cells are susceptible to Venezuelan equine encephalitis virus. Multi-omics analyses demonstrate that viral infection induces translational shutoff, downregulates Rho GTPase pathways, and reduces actin cytoskeleton dynamics, culminating in impaired neurite outgrowth and cellular migration defects.
Shotgun secretomics further confirm the downmodulation of key neurite outgrowth proteins, including midkine, amyloid-beta precursor protein, and microtubule-associated protein 1B. These mechanistic insights highlight how the virus disrupts normal brain development and establish human neurospheres as viable experimental platforms for screening teratogenic viral effects.
We hope to expand the biodefense countermeasures toolbox for pathogenic select agents and develop medical interventions that can be scaled up quickly if and when needed.
Dr. Victor Ogungbe, an associate professor of chemistry and UAH alumnus